The long term goals of this research project is to design and discover novel peptide and peptidomimetic opioid and opioid-substance P ligands with novel biological profiles at opioid receptors (and/or substance P receptors) which are potent analgesics, but which have no or minimal addiction potential, and none of the toxic side effects of current opioid, and which have novel mechanism of biological activity which can address the problems of neuropathic pain and tolerance to opioids. For this purpose, we are utilizing and further developing a comprehensive approach that involves computer assisted design of novel biostable ligands, asymmetric synthesis novel amino acids and beta-turn mimetics, and peptides and peptidomimetics with unique conformation and topographical properties; development of opioid ligand conjugates and prodrugs with unique properties; and computer aided evaluation of a variety of biophysical studies of the conformational and topographical and dynamic properties of the novel compounds. To pursue these goals we have the following specific aims: 1) optimize the design of biphalin to determine structural correlates of exceptional potency, prolonged analgesia and no respiratory depression or other toxicities; 2) develop chimeric mu/delta opioid receptor agonist that also are substance P receptor antagonists (or CGRP antagonist); 3) explore design and asymmetric synthesis of novel topographically constrained amino acid and beta-turn mimetics; 4) utilize biophysical methods (X-ray, NMR, CD, etc.) to evaluate constrained peptide and peptidomimetic, and especially to further develop the new method, coupled plasmon waveguide resonance (CPWR) spectroscopy which for the first time allowances to study the structural changes of G-protein coupled receptors such as the opioid receptor which then interacts with ligands parallel and perpendicular to the membrane normal; and 5) examine novel conjugates of our best opioid peptide ligands as conjugates with cell penetrating peptides.